THE "NEW" PROSTATE CANCER INFOLINK

The “Warnings and Precautions” section of the product prescribing information for enzalutamide (Xtandi) includes the following statement:

Seizure occurred in 0.5% of patients receiving XTANDI. In patients with predisposing factors, seizures were reported in 2.2% of patients. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

However, the developers of enzalutamide have long believed that enzalutamide could be used to treat men with mCRPC and with predisposing risk factors for seizures, so long as these men were being appropriately monitored, because the drug did not actually increase risk for seizures in these patients.

Data from the newly published UPWARD trial (reported by Slovin et al.) would appear to support the developer’s beliefs.

In this study, the research team enrolled 423 patients with mCRPC who were being treated with enzalutamide at the standard daily dose of 160 mg/d. Of these 423 patients, 366 were evaluated. Here are the study findings:

• At study baseline
  • 242/423 patients (57.2 percent) were taking drugs other than enzalutamide known to lower the threshold for seizure.
  • 112/423 patients (26.5 percent) had a history of brain injury.
  • 94/423 patients (22.2 percent) had a history of cerebrovascular accident or transient ischemic attack.
• Among the 366 evaluable patients treated with enzalutamide
  • 4/366 patients (1.1 percent) had at least one confirmed seizure within 4 months of initiation of enzalutamide treatment.
  • 3 of the remaining 362 patients (0.8 percent) had a confirmed seizure within the 4-month period after the initial 4-month study period.
  • The incidence of confirmed seizures was 2.6 per 100 patient-years.
• Among the entire patient cohort
  • 357/423 patients (84.4 percent) had at least one treatment-emergent adverse event or TEAE (i.e., and adverse event temporally associated with treatment on study).
  • 143/423 patients (33.3 percent) had at least one serious TEAE.
  • 29/423 patients (6.9 percent had at least one serious, and drug-related adverse event.
• 38/423 patients (9.0 percent) were reported to have died either during treatment or within 30 days of drug discontinuation.
• 4/38 deaths were considered to have been possibly drug related.

The incidence of seizures in this study (at 2.6 seizures per 100 patients years) was closely comparable to the incidence of seizures among a different, large cohort of US patients who had mCRPC and similar seizure risk factors, but no exposure to enzalutamide (at 2.8 per 100 patient-years); see Dharmani et al.

The authors conclude that:

Incidence of seizure is similar in patients with mCRPC and similar seizure risk factors with or without enzalutamide exposure. The risk profile presented, along with the previously established efficacy of enzalutamide, suggests that enzalutamide can benefit patients with a history of seizures or other predisposing factors, but each patient should be closely monitored for the duration of treatment.

What this paper shows, therefore, is that while there is indeed a small risk for seizures from treatment with enzalutamide among men with mCRPC who have no known risk for seizures, this does not necessarily imply that treatment with enzalutamide will increase risk for seizures among men with mCRPC who do have a known history or predisposing risks for seizures (compared to no treatment with enzalutamide).

Whether these data will be sufficient for the FDA to make any adjustments to the prescribing information for enzalutamide is beyond your sitemaster’s pay-grade, however.

Filed under: Living with Prostate Cancer, Management, Treatment, Uncategorized | Tagged: enzalutamide, risk, safety, seizures, Treatment |